As the epidemic of obesity continues unabated, infectobesity, obesity of infectious origin, has been receiving increasing attention in the recent years (Rossner S., Lakartidningen. 102(24-25):1896-8 (2005); Astrup A., et al., Int J Obes Relat Metab Disord., 22(4):375-6 (1998); Powledge T M., Lancet Infect Dis., 4(10):599 (2004)). Although many factors contribute to the etiology of obesity, a subset of obesity may be caused by infections. In the last two decades, 10 obesity-promoting pathogens have been reported (Dhurandhar N V, et al., Genetics and Hormones, 20(3): 33-39 (2004)). The first human virus, adenovirus type 36 (Ad-36), was reported that caused obesity in experimentally infected animals (Dhurandhar N V, et al., Int J Obesity, 24: 989-996 (2000); Dhurandhar N V, et al., Int J Obesity, 25:990-996 (2001); Dhurandhar N V, et al., J Nutrition, 132:3155-3160 (2002)) and showed association with human obesity (Atkinson R L, et al., International Journal of Obesity, 29:281-286 (2005)). In-vitro experiments have shown that Ad-36 infection of rat preadipocytes (3T3-L1) and human preadipocytes promote their proliferation and differentiation (Vangipuram S D, et al., Obesity Research, 12:770-777 (2004)).
Ad-36 stimulates preadipocytes (pre-fat cells) to differentiate into adipocytes (fat cells), and increases the number of fat cells and their lipid content (Id.). Ad-36 can induce differentiation of preadipocytes even in absence of conventional differentiation inducers such as the cocktail of methyl isobutyl xanthine, dexamethasone, and insulin (MDI). A similar effect of the virus is observed in human adipose derived stem cells (Id.). Rats infected with Ad-36 showed greater adiposity but paradoxically lower insulin resistance 7 months post-infection (Pasarica M, et al., Obesity Research, 12 (supplement):A122 (2004)). Moreover, fat cells from uninfected rats when infected with Ad-36 show increased glucose uptake, indicating greater insulin sensitivity (Dhurandhar N V, et al., Obesity Research, 11:A38 (2003)).
Factors required for increased insulin sensitivity include greater preadipocyte number and differentiation, and activation of cAMP and insulin signaling pathway enzymes (e.g., phosphotidyl inositol-3 kinase (PI3K or PI3 kinase)). Preadiopcyte differentiation in turn is modulated by activation of PI3 kinase and cAMP signaling pathways (Hansen J B, et al., J Biol Chem. 276(5):3175-82 (2001); Reusch J E, et al., Mol Cell Biol. 20(3):1008-20 (2000); Chiou G Y, et al., J Cell Biochem. 94(3):627-34 (2005); Cornelius P, et al., J Cell Physiol. 146(2):298-308 (1991); Burgering B M, et al., Nature 376(6541):599-602 (1995); Magun R, et al., Endocrinology 137(8):3590-3 (1996)). Ad-36 has been shown to increase preadipocyte replication, the number of differentiated adipocytes, and PI3 kinase pathway (Pasarica M, et al., FASEB J 19(4):A70 (2005)).
The liver has a predominate role in fat metabolism and normally accumulates lipids (fat), but only to “normal levels.” Excessive lipid accumulation in hepatocytes results in hepatic steatosis, which is metabolically harmful and can result from a variety of liver dysfunctions, such as decreased beta-oxidation or decreased secretion of lipoproteins. Another of the many functions of the liver is to release glucose into circulation. In healthy individuals, liver cells release glucose regularly to regulate blood glucose levels. In contrast, in individuals with diabetes, liver cells release glucose uncontrollably, which increases blood glucose levels. Therefore, reducing glucose release from liver cells (hepatocytes) can be very effective in controlling diabetes.
Excessive lipid accumulation in the liver may contribute to insulin resistance, a condition in which insulin has decreased effectiveness lowering blood sugar, and thus poor glycemic control. Adiponectin, a protein secreted by fat tissue (adipose tissue) improves insulin sensitivity in many ways. Adiponectin acts via adiponectin receptors AdipoR1 and AdipoR2 in the liver to activate AMPK and PPARα pathways (Heiker, J. T. et al. Biol. Chem. 391:1005-1018 (2010)), to decrease systemic and hepatic insulin resistance, and to attenuate liver inflammation and fibrosis (Heiker et al.). It is a strong determinant of hepatic lipid content, as indicated by mice models of adiponectin “knock-out” or overexpression (Nawrocki, A. R. et al. J. Biol. Chem. 281:2654-2660 (2006); Kim, J Y et al. J. Clin. Invest. 117:2621-2637 (2007)). Adiponectin is thought to lower hepatic steatosis by the up-regulation of AMPK-mediated hepatic lipid oxidation (Xu, A. et al. J. Clin. Invest. 112:91-100 (2003)).
Non-alcoholic fatty liver disease (NAFLD) affects up to 20% of adults in the U.S., and includes the excessive accumulation of fat in the liver (hepatic steatosis). It is often associated with obesity and insulin resistance (Fabbrini, E. et al. Proc. Natl. Acad. Sci. USA 106:15430-15435 (2009); Deivanayagam, S. et al. Am. J. Clin. Nutr. 88:257-262 (2008)). The prevalence of NAFLD is about 70-80% in adults with type 2 diabetes or obesity (Targher, G. et al. Diabetes Care 30:1212-1218 (2007); Bellentani, S. et al. Dig. Dis.; 28:155-161 (2010); Parekh, S. et al. Gastroenterology 132:2191-2207 (2007)), 3-10%, in all children, and up to 40-70% in obese children (Bellentani et al.). NAFLD is associated with greater overall and liver-related mortality (Adams, L. A. et al. Gastroenterology; 129:113-121 (2005); Ekstedt, M. et al. Hepatology 44:865-873 (2006)). In addition to steatosis, inflammation and fibrosis can develop and NAFLD may progress to non-alcoholic steato-hepatitis (NASH), cirrhosis, liver failure and hepatocellular carcinoma. While steatosis is potentially reversible, once it progresses to NASH, there are no established treatments, and the few available medications show limited success (Gupta A. K. et al. J Diabetes Complications 2009; Sanyal A. J. et al. N Engl J Med (2010) 362:1675-1685). Therefore, the timely prevention and/or treatment of hepatic steatosis is critical. However, even for NAFLD, drug treatment has marginal success (Duvnjak M., et al. J Physiol Pharmacol (2009) 60 Suppl 7:57-66), and reducing dietary fat intake and obesity are the mainstay of treatment (Mishra P. et al. Curr Drug Discov Technol (2007) 4:133-140). Despite the obvious health benefits, compliance with lifestyle changes to achieve sustained improvements in diet or obesity has proved challenging for the general population.
While excess adiposity or a high fat (HF)-diet are risk factors for NAFLD, Adenovirus 36 (Ad36) attenuates hepatic steatosis in mice despite a continued HF-diet and without a reduction in visceral or subcutaneous adiposity. Ad36 appears to qualitatively alter the metabolic quality of adipose tissue to attenuate HF-diet induced hepatic steatosis. This change in the metabolic quality of adipose tissue by Ad36 includes greater uptake and reduced release of fatty acids and greater adiponectin secretion (Rogers, P. M. et al. Diabetes (2008) 57:2321-2331; Pasarica M. et al. Stem Cells 2008 26:969-978). The thiazolidinedione (TZDs) class of drugs can also improve metabolic quality of adipose tissue, up-regulate adiponectin, and improve hepatic steatosis (Nawrocki, A. R. et al. J Biol Chem (2006) 281:2654-2660; Lutchman G. et al. Clin Gastroenterol Hepatol (2006) 4:1048-1052; Shen, Z. et al. Am J Physiol Gastrointest Liver Physiol (2010) 298:G364-374). However, serious side effects of TZDs have been reported (Habib, Z. A. et al. J Clin Endocrinol Metab (2010) 95:592-600; Ramos-Nino, M. E. et al. BMC Med (2007); 5:17; Lipscombe, L. L. et al. JAMA (2007) 298; 2634-2643).
Ad36 does not cause morbidity or unintended mortality in animals. In addition, Ad36 appears to have distinct advantages over the action of the TZDs, particularly in the presence of a HF-diet. Unlike the TZDs, Ad36 does not increase adiposity in HF-fed mice (Fernandes-Santos, C. et al. Pancreas (2009) 38:e80-86; Fernandes-Santos, C. et al. Nutrition (2009) 25:818-827). In the presence of a HF-diet, TZDs can improve glycemic control, but they concurrently promote lipid storage in various organs, including the liver (Fernandes-Santos, C. et al. Pancreas (2009) 38:e80-86; Todd, M. K et al. Am J Physiol Endocrinol Metab (2007) 292:E485-493; Kuda, O et al. J Physiol Pharmacol (2009) 60:135-140). This and other side effects limit the clinical utility of TZDs.
Harnessing certain properties of viruses for beneficial purposes has been creatively used for several years, including the use of bactericidal properties of a bacteriophage virus (Hanlon, G. W. Int J Antimicrob Agents (2007) 30:118-128), the oncolytic ability of a mutant adenovirus (Bischoff, J. R. et al. Science (1996) 274:373-376), or the use of Herpes simplex virus and several other viruses for the treatment of cancers (Crompton, A. M et al. Curr Cancer Drug Targets (2007) 7:133-139), alone, or with various synergistic drugs (Pan, Q. et al. Mol Cell Biochem (2007, 304 (1-2):315-323); Libertini, S. et al. Endocrinology 2007, 148(11):5186-5194).
Therefore, a need exists for agents that improve glucose uptake and preferably do not increase adiposity.